toni santamaria - patentes de polimorfos€¦ · in this context, the filing of patents claiming...

Toni Santamaria. Octubre 2010

"Patentes de formas polimórficas de principios activos farmacéuticos: Poli-morfismo de las patentes"

Dr. Toni SantamariaHead of Intellectual PropertyLaboratorios Lesvi S.L.INVENT FARMA

Centre de Patents. UB4 octubre 2010

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Contenido:

Aspectos regulatoriosRequerimientos de las Agencia Regulatorias

IP NomenclaturaPatentabilidadInfracción

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In this context, the filing of patents claiming new crystalline forms, usually 4-6 years after the original product patent, is a typical strategyapplied by such companies to extend patent protection. This patentprotection approach by big pharma forces generic bulk producers todiscover and file patents on new polymorphs if they want to market thedrug after expiry of the product patents.

From our direct experience, an interesting example isCabergoline (Parkinson’s disease): the originator and generic companies claimed up to 14 crystalline forms and solvates. What is the meaning of all these patent applications? Where is the advantage with respect to the previously reported crystalline forms or solvates?

Organic Process Research & Development 2007, 11, 64-724


http://www.egagenerics.com/doc/BarrerasInforme_ES_web.pdf

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CITALOPRAM HBr (CIPRAMIL ®, Lundbeck)

EP 1 169 314 and its divisional EP 1227 0088 dealing with the crystalline base of citalopramand its use for purification

The patent was granted and innovator initiated more than 30 court cases in 9 European countries.

Several generic companies faced interim injunctions and others decided simply not to enterthe market

Source: Patent-related barriers to Market entry for generic medicines in the European Union.European Generic Medicines Association. May 2008.

1[2008] EWHC 2347 (Ch) Case No: HC 06 C03050 Mr Justice Norris. 9 October2008

PERINDOPRIL ERBUMINE (Coversyl ®, Servier)

Servier has been granted patents on alpha (most thermodinamically stable), beta and gamma polymorphs ofperindopril erbumine.

UK Court granted preliminary injunctions against generic companies: Apotex, Lupin, Teva, Krka and Niche

EP1296947 was revoked by EPO after opposition and appeal (T1753/06) and by the UK Courts.

Apotex was awarded £17.5 million for damages1

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Why we are discussing about polymorphic forms in pharmaceutical products?

Characteristics of solid formsmay have influence on propertiesof the product:• bioavalability• stability• manufacture, etc.

Regulatory authorities requireinformation and characterisation ofsolid forms

Differences in propertiesbetween solid forms of the samecompound are used to justify thenovelty and non-obviousness.

Patent Protection(monopoly)

Competitors developnew forms

Pharmaceutical product

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Value of patents claiming polymorphic forms for generic companies

Even though polymorph patents may not keep a competitor completely off the market, it may still have a

comercial value if the amorphous or non-infringing crystalline form is inferior to the crystalline form (even

if it is considered bioequivalent for marketing approval):

● Usually crystalline forms are preferred for pharmaceutical compositions

● Changes in pharmaceutical form (tablets to capsules), excipients, manufacturing process or

conditions, packaging, etc.

● longer development times, less stability, etc.

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Regulatory issues. Ritonavir Case

Ritonavir is an inhibitor of HIV protease with activity against the human immunodeficiency virus.

Approved by FDA in 1996 and marketed by Abbot Laboratories

two formulations: Oral solution (80 mg/ml) and Capsules (100mg).

Soft gelatin capsules were subsequently developed.

After 2 years on the market a new thermodinamically stable polymorph began to precipitate

This proved to have lower solubility with greatly reduced bioavailability

Removal of the product from the market for almost a year

FDA CDER Chemistry review. Application No. 20-945

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm10


Regulatory requirements

Development of new active substances

ICH Q6A (http://www.ich.org/cache/compo/276-254-1.html)

3.3.1 New Drug Substances

c) Polymorphic forms: Some new drug substances exist in different crystalline forms which differ

in their physical properties. Polymorphism may also include solvation or hydration products (also

known as pseudopolymorphs) and amorphous forms. Differences in these forms could, in some

cases, affect the quality or performance of the new drug products. In cases where differences

exist which have been shown to affect drug product performance, bioavailability or stability, then

the appropriate solid state should be specified.

http://www.ema.europa.eu/htms/human/humanguidelines/quality.htm

Applicable to new drug substances (human and veterinary) and generics

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High I II

Low III IV

High Low

Solubility

Perm

eabi

lity

Biopharmaceutics Classification System (BCS)

CLASS BOUNDARIES•A drug substance is considered HIGHLY SOLUBLE when the highest dosestrength is soluble in < 250 ml water over a pH range of 1 to 7.5. •A drug substance is considered HIGHLY PERMEABLE when the extent ofabsorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose. •A drug product is considered to be RAPIDLY DISSOLVING when > 85% ofthe labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.

Dissolution rate-limiting step todrug absorption

i.e. Carbamazepine

Polymorphic forms may affectbioavailability

Important to incorporatecontrols on polymorphic forms

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm128219.htm

Dissolution proceedsrapidly. Not rate-limiting step to drug absorption

Low risk of inadvertentchange in polymorphicform to affectbioavalability

Risk of inadvertent polymorphic change

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Regulatory authorities require information on the effect of polymorphism:

• how you can be sure it is this polymorphic form and not another one, about the stability and risk ofinterconversion …

• Which polymorphic form is present in the innovator tablet?

• If it is not proved that your finished product has the same polymorphic form than innovator, you mustargue by literature articles that the polymorphic form has no influence on the solubility, bioavailabilityso on pharmacokinetic property of this active substance and consequently of the finished product.

• During ICH stability it must be proved that there is no change of the polymorphic form of active substance

• You must also prove that the manufacture process (compression) does not change thepolymorphic form of the active substance.

• A control of polymorphism at the end of shelf life should be performed.

• The possibility/ risk for conversion of drug substance to other modifications of the drug substance should be discussed.

• The influence of the polymorphic form on solubility of API, stability, melting point, etc., should be studied as physicochemical and physical characteristics may differ.

Regulatory issues

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FDA Guidance: ANDAs: Pharmaceutical Solid Polymorphism. Chemistry, Manufacturing, and ControlsInformation

Section 505(j)(2) of the Act specifies that an ANDA must contain, among other things, information to

show that the active ingredient in the generic drug product is the "same as" that of the RLD.

Specifically, 21 CFR 314.92(a)(1) provides that the term "same as" means, among other things,

"identical in active ingredient(s).“

differences in drug substance polymorphic forms do not render drug substances different

active ingredients for the purposes of ANDA approvals within the meaning of the Act and FDA

regulations.

each ANDA applicant is required to demonstrate that, among other things, the drug product exhibits

sufficient stability and is bioequivalent to the RLD.

POLYMORPHISM AND SAMENESS IN ANDAs

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Value of secondary patents in US

These patents are listed on the “Orange Book”. Patents that can be listed are:Product patentscomposition patentsuse patentspatents on polymorphic forms (Under Medicare Presciption Drug, Improvement and

modernization Act 2003)

When filing a ANDA a generic company has to certify that non of the patents listed in OB:

i) Patent information on the drug has not been filedii) Patent has already expirediii) The product will not be marketed before expiry of patents listed in OBiv) The patent is not valid or will not be infringed

FDA considers different salts a different product. Application under 505(b)(2)

More requirements than a “regular” ANDA

Not elegible for 180-days of exclusivity17


Options for developing generic drugs

Art. 10.2.(b) of EU Directive 2004/27:

“The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in propertieswith regard to safety and/or efficacy. In such cases, additional information providing proof of the safetyand/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant.”

Marketing of a different salt as generic product:

Innovator Generics

Lipitor ® Atorvastatin Calcium Atorvastatin Magnesium

Plavix® Clopidogrel Bisulfate Clopidogrel Besylate, HCl, base

Seroxat ® Paroxetine HCl Paroxetine mesylate

Norvasc ® Amlodipine besylate Amlodipine maleate

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Particular case: Orally inhaled products

New active substance are required to undergo a full development programme

regardless ot the type of device for which the new active substance is inhaled

For abridge applications….may be considered acceptable if the product satisfies all

of the following criteria (compared with the reference product):

• The product contains the same active substance (i.e. same salt, ester, etc.)

•The active substance is in the solid state (powder, suspension): any differences in

crystalline structure and/or polymorphic form should not influence the dissolution

characteristics, the performance of the product or the aerosol particle behaviour. 19



Contenido:

Aspectos regulatoriosRequerimientos de las Agencia Regulatorias

IPNomenclaturaPatentabilidadInfracción

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General Patentability requirements

According to European Patent Convention (EPC), an invention is patentable (Art. 52(1)) if :

● It is novel over the prior art (Art. 54 EPC): Prior art is defined as everything made available before the filing (priority) date of the application by means of a written or oral description, by use or in anyother way.

● It involve an inventive step

● It has industrial applicability

In US: utility, novelty and non-obviousnessBut the rules and regulations of patents differ from country to country.

For example in India, the Indian Patent Act Section 3(d) lists what are not inventions:

“The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property ….”

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General Patentability requirements

NOVELTY

In order to determine if an invention (polymorph) is patentable, the first step is to compare it with the

prior art.

Main problems to determine the (lack of) novelty:

• nomenclature of forms described

• poor description of prior art. Reproducibility (Enabling disclosure)

• Prior art disclosures difficult to locate. Hiden in regulatory information

• Prior use. Effective date??

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Nomenclature of polymorphic forms

“Part of the difficulty encountered in searching and interpreting the literature on polymorphicbehaviour of materials is due to inconsistent labelling of polymorphs. In many cases, theinconsistency arises from lack of an accepted standard notation.”

Berstein, J. Polymorphism in Molecular Crystals. 2002

“It was probably one of the low points of my career, when we spent 30 minutes arguing whether theword should be spelled co-crystal or cocrystal.[…] has even suggested quasipolymorph, and others have put forth elaborate terms such as solvatomorph, hydratomorph, and pseudopolymorphic solvate…”

War of the words. Chemical&Engineering News, 2007, 85 (25), 28-29

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Nomenclature of polymorphic forms

Inconsistent labelling of polymorph:

• Arabic (1,2,3..) or Roman (I, II, III…) numerals

• lower or upper case latin (a,b,c…or A, B, C) or lower case Greek (α,β,γ, …)

• by names descriptive of properties (red form, low-temperature polymorph,

metastable…etc)

• other:

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Inconsistent labelling. Patents and regulatory information. Aripiprazole (Abilify®)

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Inconsistent labelling. Patents of the same family: Olanzapine

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Describing polymorfic forms

It may happen that in the relevant prior art a different parameter, or no parameter at all, is mentioned. If the known and the claimed products are identical in all other respects…then in the first place an objection of lack of novelty arises.

(GL C-IV, 9.6)

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Describing polymorfic forms

Techniques to characterise crystalline forms:

ICH Q6 A.3.3.1 New drug substances.

Physicochemical measurements and techniques are commonly used to determine whether

multiple forms exist:

• Analytical Techniques

- melting point including hot-stage microscopy

- solid state IR

- X-ray powder diffraction

- thermal analysis procedures like DSC, TGA, DTA

- raman spectroscopy

- solid state NMR.

- optical microscopy28


Claiming polymorphic forms. Types of claims

EP717616

WO99/67236

WO2010/004578

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Claiming polymorphic forms

EP 993 455 B1

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EP1296947 B1

How many peaks have to be included in a claim?

• Several peaks in order to distinguish from prior art

• Few peaks to get a good protective scope.

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Value of intensities?

T1753/06. (EP1296947 B1)

“4.5.2. Le Chambre note que les diagrammes expérimetaux ainsi que le diagramme simulé, bien qu’ils soient presque identiques, présentent des légères variations….

4.5.3. …le Chambre considère que les pics ayant une intensité très faible sont les pics les plus sujets aux influences provoquées par le preparation de l’échantillon, l’appareillage pour la mesure du diagramme, les bruits de fond…

…Donc, l’intensité ne peut pas servir comme caractéristique distinctive et une variaction de l’intensité des pics dans les diagrammes expérimentaux n’indique pas la formation d’une forme cristalline différente.”


“…. I see no reason to suppose that the reader would understand the figures in the table to be of absolute precision. The reader would take a set of very similar, if not exactly similar, peaks to be those of the crystalline form claimed by the patentee. No exact match is called for.”

Perindopril UK. Servier vs. Apotex [2008] EWCA Civ 445. Supreme Court. Jacob L.J.

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Novelty. Prior art

EPO Guidelines C-IV, 9.1:

“An invention is considered to be new if it does not form part of the state of the art”

Disclosed in a single document. It is not permissible to combine separate items of prior art together

Explicitely described or implicit (may require reproduction to know what is really described)

Enabling disclosure?

Third party observations filed.Reproduction ofprior art to obtain Form I.

Patent withdrawn

“As it has never been contested that forms I and II of

Finasteride disclosed in document (1) correspond with

both presently claimed polymorphic forms, the question

arises, whether such disclosure destroys the novelty of

present Claims 1 and 2

….. in the absence of any indication of how form I may

be obtained,…

…thus, document (1) is not an enabling disclosure of

how to prepare either claimed form of Finasteride,

document (1) is not a novelty-destroying disclosure for

present Claims 1 and 2.”33

i.e. Finasteride EP0823436.- T 0605/02:


Novelty. Prior art

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Quality of figures


Novelty. Comparison with prior art

9. “…For simply comparing the cited prior art (‘341) with the patent would not reveal lack of novelty and probably not obviousness. You need the technical input of experts both in the kind of chemistry involved and in powder X-ray diffraction and some experimental evidence in order to see just how specious the application for the patent was…”.


Comparison with prior documents

Prior art does not always describe the product in a manner that can be used to compare

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Novelty. Comparison with prior art

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During process development studies it was discovered that what was initially considered a single crystalline phase, Form 1, was actually a mixture of two different forms, Form 1 and Form 3. A retrospective analysis of all the key drug substance batches clearly indicated that Form 3 was always present as minor component in mixture with Form 1. Furthermore any attempt to generate either pure Form 1 or pure Form 3 failed.


Is really possible to reproduce the prior art?

Issue (1) Anticipation by Example 4 of the acne use patent.

16. There never was any dispute what it was that Sandoz had to prove: that the inevitable result of carrying out example 4 is that the monohydrate would result. ...

18. Experience shows that some parties attacking patents simply do not follow this straightforward path. Instead they depart from the prior art. …

[2009] EWCA Civ 1188. Floyd L.J. Calcipotriol UK Appeal

Reproduction of prior art processes

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19. Here the experiment suffered from two vices. First the obvious precaution of ensuring a seed-free environment was not taken. On the contrary it was seeded (it is not suggested deliberately

so) with monohydrate (Judgment [76]). Second the recipe of example 4 was simply not followed. Why was never explained. Example 4 uses MC903 ... made by the process of

example 5 of WO/00834 ... Sandoz used calcipotriol made by a company called Teva, made by

a process which was never disclosed and devised years after the Patent. That product had different impurities.

22. The failure to use MC903 was one of the reasons why the Dutch court, Case No. 306029/HA 08-

733), refused to accept a case of inevitable result (see 4.6). […]

23. The Judge did not think the failure to start with MC903 was in itself fatal. He thought that the

skilled team would read the example as saying “start with the anhydrate compound howsoever

made”. But that meant, he reasoned, that Sandoz had to show that howsoever the anhydrous calcipotriol was made (and so with an undefined range of possible impurities) the inevitable result would be the monohydrate. The target was much bigger than if you had

to use MC903. And Sandoz had simply failed even to attack that wider target.

Reproduction of prior art. Inevitable result.

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At which scale has to be reproduced?

laboratory scale?pilot plant/ industrial?

Perindopril UK Case. Servier sued Apotex and others for infringement of EP-1.296.947-B1.

Apotex alleged that following the EP308341 the alpha form would inevitably be produced.

26. I turn to the experiments conducted for the purpose of this case. Apotex relied on four. Three

were repeated at the request of Servier. Because experience has shown that experiments

conducted for the purpose of litigation are apt to be biased, under English procedure, a party

who wishes to rely upon an experiment which he has carried out, must give notice to the other side

giving details and he must allow the other side to see a repetition of the experiment if it so

wishes.

Here Apotex relied on two experiments. Experiment 1 was on a laboratory scale and

Experiment 2 on scale of '341 (which was called "pilot"). These were repeated with Servier

representatives present. So there were four in all relating to '341.

Reproduction of prior art.

[2008] EWCA Civ 445. Jacob L.J. Perindopril UK Appeal39


Prior art does not provide clear indications on the conditions to be used


Time of reflux?

Cooling rate?

Final temperature?

In Apotex case, the protocol for the experiments was created by an independent expert who hadbeen provided with ‘341 but not the patent in suit.

EP-308.341-A

The person reproducing the prior art has to:

•use the common general knowledge at the “prior art date”•can not invent to reach at the desired product

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Prior art does not provide clear indications on the conditions to be used


Mr. Justice Pumfrey ([2007] EWHC 1538 (Pat). Perindopril. Servier vs. Apotex:

“For the purpose of anticipation, the prior documents must enable something which inevitably falls within the claim.

Where the prior art does not describe the end to be achieved, it is illegitimate to employ a refinement of

technique or whatever to cause the desired result to be achieved. Where the sufficiency of a disclosure of a

method is under discussion, of course the skilled person is entitled to do such preliminary work and carry out

such uninventive refinements, without undue effort, with a view to producing a product falling within the

claim.”

T1753/06. R.4.13: “Le chambre ne peut pas contester que l’exemple 3D du document (1) ne divulgue pas en détail le

mode de filtration, de refroidissement et de séchage, étapes qui sint en général usuelles. Par conséquent, l’homme du

metier en reproduisant l’exemple antérieur doit determiner de la façon de mettre en oeuvre ces étapes compte

tenu de ses connaissances générals et du but à atteindre dans le document considéré…”

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Novelty. Prior use

Information made available by Regulatory agencies on web sites:

European Medicines Agency (EMA): http://www.ema.europa.eu

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FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm


Novelty. Prior use

Also available for veterinary products

http://www.ema.europa.eu

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The main problem is to prove the publication date


Novelty. Prior use

EP1467712B MicardisPlus®the opponent tries to use the information published at FDA website as prior art

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Novelty. Inherent anticipation. Paroxetine (1/3)

US. Paxil®.

Paroxetine hydrochloride anhydrate. First prepared in 1970 by Ferrosan .

During scale up a new form of Paroxetine hydrochloride appeared.

Hemihydrate of Paroxetine HCl marketed since 1983

Court of Appeals of Federal Circuit: Patent invalid:

Clinical trials: Prior use (reversed)

Inherent anticipation (similar to EP implicit disclosure)

Apotex filed an ANDA to market Paroxetine HCl anhydrate containing a PIV certification (patent not infringed)

District Court: Found patent valid but not infringed

GSK asserted that Apotex will infringe by manufacturing PHC anhydrate tablets that

necessarily contain, by a conversion process discussed below, at least trace amounts of PHC

hemihydrate

Expiry dates in USA

Hemihydrate: 2006

Anhydrate: 1992

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To show that manufacture of PHC anhydrate tablets necessarily creates PHC hemihydrate, SmithKline

proffered expert testimony on the so-called "seeding" or "disappearing polymorph" theory. Under this

theory, Ferrosan may have originally created a crystalline compound, namely PHC anhydrate, in a

relatively unstable form. For presently unknown reasons, the PHC anhydrate "morphed" into a more

stable form, namely the PHC hemihydrate discovered in SmithKline's facilities. With this new form or

polymorph in existence, SmithKline's experts explained, the general environment became "seeded" with crystals of PHC hemihydrate. In this seeded environment, the PHC anhydrate converts to thePHC hemihydrate upon its inevitable contact with seeds of PHC hemihydrate. In other words, thecreation of pure PHC anhydrate became extremely difficult, if not impossible; the old polymorph, PCH anhydrate, has effectively disappeared in its pure form because it changes naturally into thenew polymorph, PCH hemihydrate.

SmithKline argues that practicing the '196 patent infringes claim 1 of the '723 patent, but that the '196

patent does not anticipate claim 1 of the '723 patent. SmithKline uses the "disappearing polymorph"

theory to justify its apparently inconsistent positions. …

403 F.3d 1331 . U.S. CAFC. 8 April 2005,


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The record shows, and SmithKline admits through its proffered arguments, that producing PHC anhydrate according to the '196 patent inevitably results in the production of at least trace amounts ofanticipating PHC hemihydrate.

…..this court holds, based on the undisputed facts, that claim 1 of the '723 patent is invalid for inherent anticipation by the '196 patent under § 102(a). Apotex is, therefore, not liable for infringing claim 1 of the '723 patent. This court affirms the district court's judgment.

403 F.3d 1331 . U.S. CAFC. 8 April 2005,


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Novelty. Reproduction of prior art. Inevitable result

“Seed crystals, they’re in the air. You can’t see them. You can’t smell them. You can’t taste them. You also can’t detect them, they’re there, and these seed crystals fall out of the sky, and they’re very intelligent because they know when you are running one of these Example 32 experiments. They fall out of the sky and fall in your reaction beaker...Well I submit that if one believes in Santa Claus we might believe in these seed crystals, but if we’re beyond that, we’re not going to believe in these seed crystals . . .”

Part of the opening statement by the counsel for Novopharm in the first ranitidinehydrochloride case against Glaxo in August 1993.

Bernstein J. Chap. 14. Polymorphism in the Pharmaceutical Industry. Ed. Rolf Hilfiker

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Inventive Step

EPO Guidelines, C-IV.11.1 General

An invention is considered as involving an inventive step if, having regard to thestate of the art, it is not obvious to a person skilled in the art. Novelty (see IV, 7) and inventive step are different criteria. The question – "is there inventive step?" –only arises if the invention is novel.

“It is at least this author’s opinion that every compound has different polymorphic forms and that, in general, the number of forms known for a given compound is proportional to the time and money spent in research on that compound.”

McCrone 1965. In Bernstein J. Polymorphism in Molecular Crystals.

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Obviousness

Problem-and-solution approach

(Usually) same compound, for the sametechnical purpose, different crystalline, ornon-crystalline or undefined form.

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Provide alternative stable form of a known compound to achieve the same effect

ObviousUnexpected or non-

obvious effect required

Provide further form of known compound with

different property

No reasonable expectation

No obvious


Surprising technical effect over prior art?

Inventive step. Surprising effect

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Alpha

EP 1 296 947 B1

(22) Date de dépôt: 06.07.2001

(30) Priorité: 06.07.2000

Gamma

EP 1 296 948 B1

Beta

EP 1 294 689 B1


Inventive step. Obvious to try?

WO2005080381

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Obviousness

Having regard to Regulatory issues is obvious to perform a polymorphism screening?

ICH Q6A

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Common General Knowledge

• The common general knowledge would include the basics of crystallisation as follows.

• A compound is said to exist in polymorphic form if it crystallises into more than one arrangement in the crystal lattice.

• It was well known and accepted that different crystal forms of the same compound (whether true polymorphs or solvates or hydrates) can have different physicochemical properties.

• These properties include solubility, dissolution rate, stability and processing characteristics. In consequence the bio-availability of the drug can be dependent on the crystal form as well.

• In general, crystallisation is an empirical process. It is not possible to predict in advancewhether a particular compound will crystallise, or whether it will form an amorphous solid.

• A given compound may fail to crystallise even where similar compounds are known to crystallise. If a given compound crystallises in one way, it is not possible to predict what if any other forms it might exist in, or whether it will form solvates.

• Inducing a compound to crystallise for the first time, or into a new crystalline form, involves choosing the correct conditions which themselves cannot be predicted in advance.

• Seemingly trivial matters such as impurities, may influence the result.

About crystal forms

Mr. Justice Floyd. [2009] EWHC 996 (Pat). UK Patents Court . Leo vs. Calcipotriol54


Common General Knowledge

About screening for polymorphs

• A polymorph screen involves crystallising an API from a variety of solvents and solvent mixtures and characterising the resulting crystals for evidence of polymorphism or pseudopolymorphism.

• Nevertheless, well before 1993, standard formulation textbooks were teaching with varying degrees of emphasis that, in the preformulation stage of pharmaceutical development, one should actively look for polymorphs

• The immediate objective in looking for alternative crystal forms is not research conducted solely or even primarily to find something better. The objective is to establish that when you make and sell the product it is not going to change into something different. …. Nevertheless, as we shall see when we come to the relevant regulatory guidelines, what is said to be important is to demonstrate stability under the actual process and storage conditions. To look more widely for polymorphs would not be regarded by the skilled team as mandatory.

• I conclude that the skilled team would know in 1993, as part of its general knowledge, that full polymorph screening was an available step to take …. That does not mean that it would be obvious to conduct such a full polymorph screen in all circumstances. The skilled team would consider in any individual case how difficult such experiments were, and the prospects of finding useful results. However, the skilled team would appreciate the importance of checking for the possibility of polymorph or solvate formation under the actual process and storage conditions proposed

Mr. Justice Floyd. [2009] EWHC 996 (Pat). UK Patents Court . Leo vs. Calcipotriol55


Obviousness

Calcipotriol Appeal. Jacob L.J. Accepted that:

•full polymorph screening using a range of solvents and conditions was a systematic investigationto discover whether a compound came in other forms.

•This process was not required by regulators

•Crystallising analogues was difficult and that Leo Pharma’s past experience had not indicated it was worthwhile for any purpose at all.

•It was not universal practice to conduct a polymorph screen

•The skilled team would not regard such a screen as mandatory

CONCLUSION: THE SKILLED TEAM WOULD NOT CARRY OUT A FULL SCREEN

NOT OBVIOUS

Source: Bratin Roy. Leo Pharma A/S vs Sandoz Ltd.- Whither the Single European Patent. Europ. Int. Prop. Rev. 2010, 178. 56


Obviousness

“In my opinion, the evidence of the state of the knowledge at the date of the invention, that is

the discovery of the hemyhidrate form and the fact that it had beneficial properties for the

manufacture of crystalline paroxetine hydrochloride, does not indicate that others skilled in

the art would have known the way in which to create, notice and document the benefits

of the hemihydrate form….

As noted above, the test for obviousness is stringent. It requires the capable but non-

imaginative skilled person to look at the common knowledge in the art at the date of the

invention and immediately, without imaginative ingenuity, reach at the described

invention.”

57SKB vs Genepharm. Paroxetine (Canda). Ms. Heneghan J. 2003 FC 1248


Challenging the validity of patents

When and where?

• During examination by filing Third party observations (Art. 115 EPC).

• After grant: filing an opposition (Art.100 EPC).

• After opposition: invalidation proceedings before national courts.

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Problems:

● In some countries infringement and validity are assessed separately● Different Courts may reach at a different conclusion


Challenging the validity of patents

In Calcipotriol case. (EP (UK) No. 0 679 154

High Court of Justice. Patent Court. Mr. Justice Floyd:

“The parties are in dispute over the Patent elsewhere. The Dutch court, has rejected Sandoz’ invalidity attack …... a German court had held the patent invalid on the basis of an obviousness attack different to the one pursued before me. …... If there were a supra-national court of the kind currently proposed, able to decide on disputes about the validity of patents for the whole of Europe, conflicting results of this kind between courts of first instance could be avoided.”

High Court of Justice. Court of Appeal. Jacob L.J.:

“This appeal falls to be dismissed. I only add a couple of points. This is yet another case where validity has to be assessed by several national courts. We have reached the same result as that in Holland at first instance (where the argument was in part different). The Bundespatentgericht has gone the other way – but working on different prior art, prior art which Sandoz in this country abandoned. Different results in different countries based on different cases is, of course, explicable. It is an unfortunate state of affairs, curable only by a single European Patent Court.”

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Infringement of patent claiming polymorphs

US. Paroxetine SKB vs. Apotex

District Court

… limited claim 1 to PHC hemihydrate in commercially significant amounts. …. The trial record contained uncontested testimony that a PHC anhydrate-hemihydrate mixture would need to possess a percentage of PHC hemihydrate in the "high double digits" if the hemihydrate component were to contribute any commercial value. …

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Federal Circuit:

Having interpreted claim 1 to cover PHC hemihydrate without further limitation,

In summary, this court reverses the claim construction of the district court and holds that claim 1 of the'723 patent covers any amount of crystalline paroxetine hydrochloride hemihydrate without furtherlimitation. … this court affirms the district court's finding that Apotex's PHC anhydrate product will infringe claim 1


66] In construing the claim in issue, the Court must identify the essential elements of that claim. …

The key to purposive construction is therefore the identification by the court, with the assistance of the skilledreader, of the particular words or phrases in the claims that describe what the inventor considered to be the"essential" elements of his invention...

[67] … that task is challenging since the claim contains only four words and reads as follows: "crystalline paroxetine hydrochloride hemihydrate".

[68] … We have found that amorphous paroxetine hydrochloride is a hygroscopic solid of poor handling qualities.

The purposive approach to construction ….. The hemihydrate is described as being stable and non-hygroscopic …. It is not sensible to interpret the claim as covering minuscule and minute amounts of crystalline paroxetine hydrochloride hemihydrate which, according to the expert evidence, is now extremely widespread since the discovery of the product in 1984, due to the prevalent use of the drug and the factors of seeding and conversion.

[75] … Claim 10 means crystalline paroxetine hydrochloride hemihydrate when it is found in a drug in sufficient quantity that it improves the handling properties of such drug during manufacture.

Source: http://decisions.fct-cf.gc.ca/en/2003/2003fc1248/2003fc1248.html

Infringement Canada

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• Usually a polymorph is not a new product. It is a new physical form of a known chemical product.

• It is developed to solve a techical problem

• A different polymorphic form, may not solve the same problem at all

Claim Construction.

According to Art. 69 EPC and its protocol for interpretation:

•Scope determined by claims

•Description used to resolve ambiguities

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Which is the maximum amount of polymorph B (patented) in a pharmaceutical composition ofpolymorph A (Free)?

B is patentable (probably) because of the new properties/features and solve a techincal problem that A doesnot solve

Trace amounts of B (claimed polymorph) in A is an act of infringement?

• In US: YES • In Canada: No• in EU???

•Which levels are detectable? • Which technique has to be used to determine the presence of patented polymorph?• limit of detection?

• The presence of traces may have a seeding effect. Polymorphic stability has to be proved over theshelf life of the product (Regulatory requirement!!!)

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Regulatory

It is important to characterise the crystalline forms and to know their properties

Consider the risk of inadvertent change of polymorphic forms and its effect on the product

Value for patentees

Follow-up patents are useful to keep off competitors from market or to delay their entry

Patentability

There is no standard or generally accepted notation for polymorphs

Prior art descriptions usually does not provide enough information to compare with newinventions

Although there are systematic approaches to polymorph screening is not obvious to performthem and to understand the results obtained

Conclusions

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Litigation:

Prior art disclosures. Repeat exactly the prior art process (if possible!!):

● same scale

● using same procedure

● Impurities……

Environment is seed-free

claim construction???

Conclusions

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Conclusions

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9. The upshot of all this is that were the patent valid, Servier’s monopoly in practice

would last until 2020. But, as the Judge held and we confirm, it is invalid. And very

plainly so. It is the sort of patent which can give the patent system a bad name. I am

not sure that much could have been done about this at the examination stage. There

are other sorts of case where the Patent Office examination is seen to be too lenient.

But this is not one of them. For simply comparing the cited prior art (‘341) with the

patent would not reveal lack of novelty and probably not obviousness. You need the

technical input of experts both in the kind of chemistry involved and in powder X-ray

diffraction and some experimental evidence in order to see just how specious the

application for the patent was. The only solution to this type of undesirable patent is

a rapid and efficient method for obtaining its revocation. Then it can be got rid of

before it does too much harm to the public interest.



Gracias

Preguntas ?

Dr. Toni SantamariaHead of Intellectual Property DepartmentLaboratorios LESVI S.L. INVENT FARMA GROUP___________________________________Avda. Barcelona, 6908970 Sant Joan Despi (Barcelona)[email protected]. +34 93 602 24 03Fax. +34 93 373 87 51 www.lesvi.com____________________________________

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toni santamaria - patentes de polimorfos€¦ · in this context, the filing of patents claiming...

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